Vascular diseases refer to diseases caused by a narrowing of blood vessels and/or increased vascular resistance, and cause insufficient supply of gas and nutrition to tissues because blood flow is interrupted. Causes of Vascular diseases are developed by various causes including inflammation, necrosis, vasospasm and thickening of vessel walls.
The most typical vascular disease is hypertension. Hypertension is the disease with the highest incidence rate among chronic circulatory diseases and approximately 15% of the Korean adult population are estimated to have hypertension. Hypertension refers to a case in which blood pressure is abnormally high, and causes life-threatening complications such as coronary artery diseases, stroke/cerebral infarction, heart failure, and peripheral vascular diseases. Many anti-hypertension medications have been developed to control the increased blood pressure and have different pharmacological actions with different side effects. Since the causes for the increased blood pressure are unknown in about 90% of patients with hypertension, the patients with essential hypertension use multiple medications with different pharmacological actions. Thus, many kinds of anti-hypertensive medications with different pharmacological actions are needed for the patients. Among them, a cAMP-dependent antihypertensive drug is also used, but currently prescribed is just one, iloprost, which is used to treat pulmonary hypertension. However, iloprost is available for an inhaled or intravenous form, but not for an oral form. Thus, it is necessary to develop a new cAMP-dependent hypertension medication which can be used for an oral form,
On the other hand, KCa3.1 channel is distributed in nerve cells, erythrocytes, fibroblast, proliferating vascular smooth muscle cells, endothelial cells, immune cells (T cells and B cells), and the like, and contributes to regulation of cell functions in physiological and pathological conditions. [Kaushal V. et al., 2007, J. Neurosci., 27(1):234-244; Anand U. et al., 2006, Neurosci. Lett., 399(1-2):51-56; Wulff H. et al., 2004, J. Immunol., 173(2):776-786; Wulff H. et al., 2007, Curr. Med. Chem., 14(13):1437-1457]. Abnormal (new or increased) KCa3.1 expression might contribute to pathological cellular proliferation and thereby development of various diseases. Thus, KCa3.1 channel is believed to be the target to treat diseases.
Specifically KCa3.1 channel inhibitors are known to inhibit proliferation of immune cells (T cells and B cells), fibroblasts, tumor cells, vascular smooth muscle cells and the like. [Ghanshani S. et al., 2000, J. Biol. Chem., 275(47):37137-37149; Wulff H. et al., 2004, J. Immunol., 173(2):776-786; Pena T. L. & Rane S. G., 1999, J. Membr. Biol., 172(3):249-257; Chou C. C. et al., 2008, Expert Rev. Mol. Diagn., 8(2):179-187; Neylon C. B. et al., 2004, Pflugers Arch., 448(6):613-620]. Therefore, when a drug that inhibits KCa3.1 channel was administered or KCa3.1 channel was destroyed, the proliferation of cancer cells was suppressed and the progression of atherosclerosis, renal fibrosis and post-angioplasty restenosis was inhibited. [Chou C. C. et al., 2008, Expert Rev. Mol. Diagn., 8(2):179-187; Grgic I. et al., 2009, Pflugers Arch., 458(2):291-302; Kohler R. et al., 2003, Circulation, 108(9):1119-1125; Toyama K. et al., 2008, J. Clin. Invest., 118(9):3025-3037]. Further, KCa3.1 channel inhibitors eased the symptoms of autoimmune encephalomyelitis and cardiovascular diseases [Chou C. C. et al., 2008]. Therefore, substances that inhibit KCa3.1 channel are expected to be able to treat various KCa3.1 channel-mediated diseases; however, reports on substances that could effectively inhibit KCa3.1 channel are minimal.
Modafinil is currently being used to treat sleep disorders such as narcolepsy [Ballon J. S. et al., 2006, J. Clin. Psychiatry, 67(4): 554-566], and clinical tests are being performed for use in other psychiatric disorders such as cocaine dependence, attention deficit hyperactivity disorder, depression, seasonal affective disorder, bipolar depression, nicotine addiction, and schizophrenia. [Dackis C. A. et al., 2005, Neuropsychopharmacology, 30(1): 205-211; Donovan J. L. et al., 2003, Ther. Drug Monit., 25(2): 197-202; Minzenberg M. J. et al., 2008, Neuropsychopharmacology, 33(7): 1477-1502; Swanson J. M. et al., 2006, J. Clin. Psychiatry, 67(1): 137-147]. Also, some preclinical evidence indicates the possibility of modafinil use in the treatment of neurodegenerative disease, Parkinson's disease and cancer-related fatigue. [Campos M. P. et al., 2011, Rev. Assoc. Med. Bras., 57(2): 211-219; Portela M. A. et al., 2011, Curr. Opin. Support Palliat. Care, 5(2): 164-168; Wirz S. et al., 2010, Schmerz 24(6): 587-595; Zeng B. Y. et al., 2004, Neurosci. Lett., 354(1): 6-9]. Since other medications for the treatment have not yet been approved, the use of modafinil for the treatment of these psychiatric disorders is noteworthy.
In this light, because modafinil has been used as a psychostimulant for the treatment of narcolepsy, most of the research about the action mechanism of modafinil has been concentrated on the monoaminergic effect that displays modafinil stimulating histamine, norepinephrine, serotonin, dopamine, and orexin system in brain. Modafinil occupies and regulates the dopamine and norepinephrine transporters. [Madras B. K. et al., 2006, J. Pharmacol. Exp. Ther., 319(2): 561-569; Zolkowska D. et al., 2009, J. Pharmacol. Exp. Ther., 329(2): 738-746]. In addition, modafinil is known to inhibit the vitality of the human liver cytochrome p450 [Robertson P. et al., 2000, Drug Metab. Dispos., 28(6): 664-671] and to function as a neuroprotection [Anronelli T. et al., 1998, Neuroreport, 9(18): 4209-4213; van Vliet S. A. et al., 2008, Brain Res., 1189: 219-228; van Vliet S. A. et al., 2006, Behav. Pharmacol., 17(5-6): 453-462]. On the other hand, modafinil displayed the inhibition of GABA-activated currents [Huang Q. et al., 2008, Brain Res., 1208: 74-78]. However, its main action mechanism is still unclear and more research is needed to explain the effect of modafinil on cells. Furthermore, any use of modafinil for the treatment of vascular diseases or KCa3.1 channel-mediated channel-mediated diseases has not been identified prior to the present invention.
As a result of intensive research efforts to verify the possibility of modafinil as a medicine for treating vascular diseases or KCa3.1 channel-mediated diseases, the present inventors verified that modafinil increases intracellular cAMP levels, and thereby evokes relaxation of vascular smooth muscle, and KCa3.1 current inhibition by the phosphorylation of KCa3.1 channel protein. In addition, the effects to increase intracellular cAMP concentration, and thereby to induce vascular smooth muscle relaxation and KCa3.1 current inhibition have been identified in the novel derivatives thereof, thereby completing the present invention.